Para-selective nitrobenzene amination lead by C(sp2)-H/N-H oxidative cross-coupling through aminyl radical

Arylamines, serving as crucial building blocks in natural products and finding applications in multifunctional materials, are synthesized on a large scale via an electrophilic nitration/reduction sequence. However, the current methods for aromatic C–H amination have not yet attained the same level of versatility as electrophilic nitration. Here we show an extensively investigated transition metal-free and regioselective strategy for the amination of nitrobenzenes, enabling the synthesis of 4-nitro-N-arylamines through C(sp2)-H/N-H cross-coupling between electron-deficient nitroarenes and amines. Mechanistic studies have elucidated that the crucial aspects of these reactions encompass the generation of nitrogen radicals and recombination of nitrobenzene complex radicals. The C(sp2)-N bond formation is demonstrated to be highly effective for primary and secondary arylamines as well as aliphatic amines under mild conditions, exhibiting exceptional tolerance towards diverse functional groups in both nitroarenes and amines (>100 examples with yields up to 96%). Notably, this C(sp2)-H/N-H cross-coupling exhibits exclusive para-selectivity.

2. The introduction is broad and well-written, but I think the discussion about Professor Baran's work doesn't fit with this paper and might confuse readers.This paper talks about making a C-N bond between the ring's Sp2 carbon and an amine.In Professor Baran's paper, anilines are made by a different process, which is a formal alkylation of the nitro group.I suggest removing it.
3. The authors should reference and discuss three significant studies in the introduction that describe the CH amination of electron-poor arenes, including nitrobenzene, through radical chemistry: Ritter et al. in Chemical Science, 2019, 10, pages 2424-2428;Ritter et al. in Angewandte Chemie International Edition, 2019, 58, pages 532-536;and Carreira et al. in Angewandte Chemie International Edition, 2019, 58, pages 526-531.I am surprised that this paper are completely omitted considering the relevance with the reported reaction.
4. The authors should address the synthesis of nitroaniline through SnAr on Sp2 C-H bonds.This is important because these kinds of reactions are rare but use very similar conditions.(ex:J. Org.Chem. 1998, 63, 4878-4888,Chem. Commun., 2016, 52, 7237-7240 , Synthesis 2010, 22, 3865-3872, Journal of the Chemical Society 1932, 1254-1261) 5.When addressing the research of Professor Ritter and Professor Leonori, the authors should revise their statement."Morerecently, direct radical amination strategies have showed particular innovation, but they are usually applied to electron-rich aromatics due to the essence of the electron-deficient nitrogen radical" to electron-rich and electroneutral, for example Fluorobenzene is effectively aminated in these works together with other electron neutral arene.
7. The authors have reported a considerable number of amines, yet the scope is notably redundant.Mainly, 1,2,3,4-tetrahydroquinoline and indoline are featured, and the substitution pattern on the aromatic ring is limited, with only halogens, alkyl ether, and methyl group.Could the authors provide at least 5 examples where other functional groups are incorporated onto the ring?It would be beneficial to see if functional groups such as cyanide, ester, ketone, trifluoromethyl, boronic ester, azide, thioether, sulfone, and amide are compatible with the reaction.
8. Methyl phenyl alanine is well represented, but in a repetitive manner.Could the author provide 5 additional examples where the methyl group is replaced with different aliphatic chains or groups.9.In the abstract, the authors state that they have achieved coupling with primary arylamines and aliphatic amines, but only two examples of each are provided in the scope.Could the author provide 5 additional examples for each of these categories (5+5), as they are important building blocks and while really demonstrate the generality of the protocol.10.Do primary aliphatic amines not react?If that is the case, can the authors specify this as a limitation of the protocol in the main text.
11. Regarding the aromatic scope, the authors tested three categories of amine for each nitroarene, but the number of nitroarenes used is very limited, with only 14 examples.I would prefer to see reactions of just 1,2,3,4-tetrahydroquinoline, but with more diversity among the nitroaromatics.Can the authors include at least another 5 to 8 different nitroarenes in the scope?It would be interesting to see if functional groups such as cyanide, ester, ketone, trifluoromethyl, boronic ester, azide, thioether, sulfone, and amide are compatible with the reaction.
12. What happens when para-nitrotoluene and parafluorobenzene react?Can the authors report the outcome of such a reaction?Does the selectivity change, or does the reaction not work?Could the author provide this information?13.Would the author consider rephrasing this sentence for clarity?''It formally seems to be an SNArH reaction, however, as shown in our optimization experiments that the reaction proceeds only in the DMSO/tBuONa/O2 or DMF/tBuOK/O2 system, which is characterized by the presence of alkali metal ion as a possible mediator of further reactions via single electron transfer (SET) from a reactant to generate the free radicals of the latter.
14. Could the authors please provide references to substantiate the claim that tBuONa or tBuOK serves as a mediator in reactions proceeding via single electron transfer, as mentioned in lines 161-162-163 15.Can the author provide a proper citation to support the statement made at lines 182-183.''The reaction can give azobenzene 6d with aniline 5d from radical homo-coupling under standard conditions, indicating the nitrogen radical'' 16.Could the authors repeat the experiment in fig 2g for synthesizing azobenzenes with methyl aniline, as reported in the manuscript, since there are no examples using simple aniline.17.Could you please elucidate how the experiments shown in Figures 2h, 2j, 2k, and 2l relate to the mechanism under discussion?Presenting these experiments without deriving conclusions may lead to confusion.It may be more appropriate to relocate this information to another section or include it in the Supplementary Information.Particularly the reaction in Figure 2h appears to have an energy profile (S40 in the SI) that closely resembles that of nitrobenzene could the author provide an explanation?18.The Radical clock experiment reported in Fig 2m did not provide any product that prove radical formation.Furthermore, the explanation offered for the formation of 6g lack experimental support.
-Could the authors clarify how they have ruled out the possibility that a simple reduction of nitroarene to form aniline, followed by the formation of compound 6g as described earlier, is not occurring?-It may be beneficial for the authors to consider repeating the experiment with a different nitroarene, such as ortho-Cl or ortho-F, or paramethyl N-cyclopropylaniline to ensure that a self-condensation reaction to form 6g as described earlier is not taking place.
19.The experiment reported on page S35 of the SI, Figure 2B, which show the mass detection of the opened radical clock is quite significant and therefore should be included in the main manuscript, since provides tentative support for the formation of the aminyl radical.To substantiate this finding, the authors are encouraged to provide the FID)from the mass spectrometry, including fragmentation patterns, in the SI.20.Would the author consider rephrasing this sentence for clarity?Line 205-207 Which radical species is the author referring to? ''Furthermore, nitrogen radical could not deliver the desired radical without tBuONa or O2, indicating that the base and O2 are all necessary for the formation of nitrogen radical.''21.At lines 207-208, the text mentions 'the obvious nitrobenzene complex radical.'Is this radical the same as the one shown in EPR Figure 3b and described as INT1 in Figure 4? For clarity, the should call it with is name and repor the structure in Figure 3b next to EPR specta.
22. Furthermore, the details about the EPR on page S33, which provide the most convincing evidence of the radical nature of the process, should be included in the main manuscript.
23. Regarding the conclusion, the authors suggest that triplet oxygen could generate nitrogen radicals through hydrogen abstraction from the N-H bond, presenting a mild and versatile pathway to N-centered radicals.However, the mechanism illustrated in Figure 4 depicts oxygen functioning merely as an oxidant for Na-amide, with triplet oxygen acting as a simple oxidant.Could the Authors clarify this point?24.In the Supplementary Information, the FID, show impurities in the aromatic region.These compounds should be further purified, and higher-quality data should be provided

Reviewer #3 (Remarks to the Author):
This manuscript by Lei and Cai reports a para-selective nitrobenzene amination.This reaction was carried out through dehydrogenative C-H/N-H cross-coupling between nitroarenes and amines in DMSO/base/O2 system through aminyl radical process.This is an interesting finding.The mechanistic studies were well designed.Considering its interesting finding, I recommend this manuscript to be published in Nat Commun after the minor revision.
1)In Figure 1b, the radical position in Baran's work should be corrected.2) In Figure 2m, the reaction of 5g with 2a gave 6g.However, 6g was also possible to be obtained from homo-coupling of 2a (see Fig. 2l).A substituted 5g is recommended for the reaction to verify the aniline moiety of 6g being from 5g.
3) How about if the para-position of nitroarenes is blocked.Can the authors provide some examples?

Reviewer #4 (Remarks to the Author):
In this manuscript, Cai and Lei et al. reported a strategy to synthesize 4-nitro-N-arylamines by C(sp2)-H/N-H oxidative cross-coupling reaction between amines and nitroaromatic compounds in DMSO/t-BuOK/O2 system.Under mild and transition-metal-free conditions, para-nitroarylamine derivatives could be efficiently obtained by this versatile synthetic method using O2 as oxidant.The mechanistic studies show that the reaction is a free radical reaction, rather than a nucleophilic attack of the amino anion to the nitroarene.This manuscript could be accepted after considering the following issues: 1.From the substrate scope in Table 1 and Table 2, the synthesis strategy is only applicable to secondary amines instead of primary amines.The range of substrate is should be corrected in the abstract.In addition, the synthesis strategy seems to rely strongly on the conjugation of aryl groups with amines.In the experiment with only four groups of aliphatic amines as substrates (3d-1, 3d-2, 1a-24, 1d-3), only tetrahydrofuran got the expected products.It can be seen that this strategy is also not suitable for aliphatic amines.2. The substrate scope in Table 1 and Table 2 only contain some simple substituent groups (alkoxy, halogen and methyl groups).The authors could try more representative substrate.Meanwhile, I wonder if the strategy be functional group tolerance or not?For example, how about the tolerance for the carboxylic acid, alcohol, amide, aldehyde, ketone and other common functional groups?3. Table 1 shows that 1,2,3,4-tetrahydroquinoline derivatives with substituents at C8 could not obtain products.Similarly, could the indole derivatives with substituents at C7 have reactivity?4. Could pyrrole be used as substrate in this strategy?5.In this work, does the nitrobenzene with substituents at C4 position react or not?And what is the role of the nitro group?Could it be replaced by other electron-withdrawing groups?6.It is no doubt that the reaction is a free radical reaction proved by the control experiment.However, the DFT calculation is confused.The energy barrier of the reaction reached 43.2 kcal/mol from 1a-1 to TS1, and the reaction could not happen under the experimental conditions.In addition, the generation of NaO2 species is suspicious.Is it a free radical?Could it be verified by experiments?
The manuscript reports on the development of a procedure for site-selective para-C(sp 2 )-H amination of nitrobenzene enabled by the DMSO(DMF)/tBuOK(Na)/O2 systems.I am sincerely amazed by the very low quality of this contribution.The manuscript is poorly written, careful editing of the entire text should have been carried out prior to submission.Moreover, the mechanistic part is confused and highly speculative, and does not provide any conclusive evidence in favor of the proposed mechanism.The manuscript cannot be accepted for publication in Nature Communications.In the present form, I would also definitely not recommend publication in a more specialized synthetic journal.
Abstract.The authors state that …"A transition metal-free and regioselective nitrobenzene amination strategy to synthesize 4-nitro-N-arylamines through dehydrogenative C(sp2)-H/N-H cross-coupling between electronpoor nitroarenes and amines in DMSO/tBuOK/O2 system is well established."Because this is actually the outcome of the present work I think that the concept of well established is not appropriate.Page 3, Results.The authors state that…."thereaction could not proceed in solvents other than DMSO and DMF."Additional details of the different solvents employed must be provided.The sentence should be probably reformulated taking into account the solvents that have been tested and could read as follows: among the investigated solvents, the reaction was observed to proceed only in DMSO and DMF.
Page 3, lines 106 and 114.What do the authors mean with relative configuration of 3a-6 and 3b-1?
Page 3, lines 109-111.The substituents are typically not allowed to give similar yields.Please replace with a more pertinent definition.
Page 4, lines 128-129.Product 6g should be displayed in Table 1 and properly quantified.Page 4, line 132.In order to help the reader, the mentioned by-products should be clearly defined.
The description of the mechanistic studied that starts at the end of page 5 is confused and often speculative.Lines 160-163: …"the reaction proceeds only in the DMSO/tBuONa/O2 or DMF/tBuOK/O2 system, which is characterized by the presence of alkali metal ion as a possible mediator of further reactions via single electron transfer (SET) from a reactant to generate the free radicals of the latter."Please elaborate, as it stands the sentence is not clear Line 166: tetrahydroquinoline Lines 175-178.The authors speculate that…."Deprotonation/oxidation of 5a yielded the aminyl radical 6a-I, where thermodynamically favorable intramolecular 1,4-hydrogen atom shift from the 4-benzylic C-H bond (Bond dissociation energy (BDE) ～ 73 kcal/mol) to the 4-aminyl radical (BDE of C-H bond ～ 89 kcal/mol) furnished the 4-benzylyc radical 6a-II."Although thermodynamically favourable, I sincerely don't see why and especially how the proposed intramolecular 1,4-hydrogen atom shift occurs Lines 192-199.The description of the radical clock experiment is pure speculation.N-Cyclopropylaniline is not an appropriate probe for the intended purpose.The putative intermediate aminyl radical is stabilized by the phenyl group and this would significantly slow down ring opening.The possible process described on the bottom-left of Figure 2  Abstract.The authors state that "A transition metal-free and regioselective nitrobenzene amination strategy to synthesize 4-nitro-N-arylamines through dehydrogenative C(sp 2 )-H/N-H cross-coupling between electron-poor nitroarenes and amines in DMSO/ t BuOK/O2 system is well established."Because this is actually the outcome of the present work, I think that the concept of well-established is not appropriate.

Our Replies:
The introduction of the design details in Panels (b)-ii and an overview of the reaction in Panels (c) would be more effective if presented separately.

Comment & Suggestions 1.3:
Page 3, Results.The authors state that … "the reaction could not proceed in solvents other than DMSO and DMF."Additional details of the different solvents employed must be provided.The sentence should be probably reformulated taking into account the solvents that have been tested and could read as follows: among the investigated solvents, the reaction was observed to proceed only in DMSO and DMF.

Our Replies:
The different solvents employed have been previously described in detail prior to this latest release.Please refer to ESI, †S17.

Comment & Suggestions 1.4:
Page 3, lines 106 and 114.What do the authors mean with relative configuration of 3a-6 and 3b-1?

Our Replies:
The phrases have been replaced with "The structure of 3b-1 was unambiguously confirmed by single-crystal X-ray analysis" and "The structures of 4a-7, 4b-8, 4b-9 and 4c-10 were unambiguously confirmed by single-crystal X-ray analysis".

Comment & Suggestions 1.4:
Page 3, lines 109-111.The substituents are typically not allowed to give similar yields.
Please replace with a more pertinent definition.

Our Replies:
Revised in this section, please refer to lines 93-105.

Our Replies:
The formation of 6g is an unexpected outcome observed in radical-clock experiments.
Additionally, the utilization of a substituted 5i compound is attempted to confirm the presence of the aniline moiety in 6i originating from 5i.And the expected product 6i-1 was determined by GC-MS in the system.Unfortunately, our attempts to isolate the target product 6i-1 were unsuccessful.
Comment & Suggestions 1.6: Page 4, line 132.In order to help the reader, the mentioned by-products should be clearly defined.

Comment & Suggestions 1.7:
The description of the mechanistic studied that starts at the end of page 5 is confused and often speculative.Lines 160-163: … "the reaction proceeds only in the DMSO/ t BuONa/O2 or DMF/ t BuOK/O2 system, which is characterized by the presence of alkali metal ion as a possible mediator of further reactions via single electron transfer (SET) from a reactant to generate the free radicals of the latter."Please elaborate, as it stands the sentence is not clear.

Our Replies:
The phrase has been replaced with "Although formally resembling an SNArH reaction, control experiments and radical clock experiments demonstrate that the reaction proceeds via a radical mechanism in the DMSO/ t BuONa/O2 or DMF/ t BuOK/O2 system".

Our Replies:
To gain mechanistic insight into this t BuOK/DMSO/O2 process, we investigated the influence of N-H bond in the reaction (Fig. 2a and 2c).Among control experiments, substrate 5a gave the 1,4-di(4-nitrophenyl) substituted product 6a with a moderate yield of 41%, while substrate 5c containing an N-substituent (N-Me) didn't react with 2a.These results underscore the essential role played by the N-H bond and suggest potential involvement of intermediates such as 6a-I and 6a-II.
Comment & Suggestions 1.10: Lines 192-199.The description of the radical clock experiment is pure speculation.N-Cyclopropylaniline is not an appropriate probe for the intended purpose.The putative intermediate aminyl radical is stabilized by the phenyl group and this would significantly slow down ring opening.The possible process described on the bottom-left of Figure 2 makes no sense.Product 6g is observed in a number of reactions where no aromatic amine is employed and this reviewer does not understand the need to propose a tentative mechanism for the formation of this product from N-cyclopropylaniline without any experimental support.

Our Replies:
The utilization of a substitute 5i is attempted to confirm the presence of the aniline moiety in 6i originating from 5i.And the expected product 6i-1 was determined by GC-MS in the system.Unfortunately, our attempts to isolate the target product 6i-1 were unsuccessful.

Comment & Suggestions 1.11:
The authors should indicate if the DFT calculations refer to gas-phase or if a solvent model was employed

Our Replies:
We optimized structures in gas-phase, and calculated single-point energies in SMD solvation model (DMSO as solvent).
Comment & Suggestions 1.12: Page 9. Discussion should be replaced by Conclusions.

Our Replies:
"Discussion" has been replaced by "Conclusions".

Response to reviewer 2' s comments
Comment & Suggestions 2.1: The paper needs to be checked by native English speaker because many parts are hard to understand.

Our Replies:
We have carefully revised our writing, and corrected grammatically incorrect sentences in our manuscript.

Comment & Suggestions 2.2:
The introduction is broad and well-written, but I think the discussion about Professor Baran's work doesn't fit with this paper and might confuse readers.This paper talks about making a C-N bond between the ring's Sp 2 carbon and an amine.In Professor Baran's paper, anilines are made by a different process, which is a formal alkylation of the nitro group.I suggest removing it.

Our Replies:
The discussion pertaining to Professor Baran's work has been omitted.

Comment & Suggestions 2.3:
The authors should reference and discuss three significant studies in the introduction that describe the C-H amination of electron-poor arenes, including nitrobenzene, through

Our Replies:
In the introduction, we have referenced these studies as 36, 37, and 38 while discussing the radical-based C-H amination of electron-deficient arenes (lines 61-64).

Our Replies:
Lines 54-56, we have addressed the aforementioned synthesis of nitroaniline via SNAr on C(sp 2 )-H bonds.

Comment & Suggestions 2.5:
When addressing the research of Professor Ritter and Professor Leonori, the authors should revise their statement."More recently, direct radical amination strategies have showed particular innovation, but they are usually applied to electron-rich aromatics due to the essence of the electron-deficient nitrogen radical" to electron-rich and electroneutral, for example Fluorobenzene is effectively aminated in these works together with other electron neutral arene.

Our Replies:
Lines 58-61, the phrase has been replaced with "More recently, direct radical C-H amination strategies have exhibited particular innovation, but challenges remain with C-H amination of electron-poor nitroarenes due to the essence of the electron-deficient nitrogen radical".

Our Replies:
The reference 30 has been removed.

Comment & Suggestions 2.7:
The authors have reported a considerable number of amines, yet the scope is notably redundant.Mainly, 1,2,3,4-tetrahydroquinoline and indoline are featured, and the substitution pattern on the aromatic ring is limited, with only halogens, alkyl ether, and methyl group.Could the authors provide at least 5 examples where other functional groups are incorporated onto the ring?
It would be beneficial to see if functional groups such as cyanide, ester, ketone, trifluoromethyl, boronic ester, azide, thioether, sulfone, and amide are compatible with the reaction.

Our Replies:
We have provided 10 additional examples.The ester group in 1a-25 underwent hydrolysis to form the carboxyl group under alkaline conditions, leading to the synthesis of product 3a-23 with a yield of 79%.

Comment & Suggestions 2.8:
Methyl phenyl alanine is well represented, but in a repetitive manner.Could the author provide 5 additional examples where the methyl group is replaced with different aliphatic chains or groups.

Our Replies:
We have provided 5 additional examples where the methyl group is replaced with different aliphatic chains or groups.
Comment & Suggestions 2.9: In the abstract, the authors state that they have achieved coupling with primary arylamines and aliphatic amines, but only two examples of each are provided in the scope.
Could the author provide 5 additional examples for each of these categories (5+5), as they are important building while really the generality of the protocol.

Our Replies:
We have provided 11 additional examples of aliphatic amines.However, the reactions involving other arylprimary amines yielded unsatisfactory results, with the prominent formation of azobenzene compounds observed as ones of defined by-products.The limitations of this type of substrates have been delineated within the main manuscript (lines 113-115).
Comment & Suggestions 2.10: Do primary aliphatic amines not react?If that is the case, can the authors specify this as a limitation of the protocol in the main text.

Comment & Suggestions 2.11:
Regarding the aromatic scope, the authors tested three categories of amine for each nitroarene, but the number of nitroarenes used is very limited, with only 14 examples.I would prefer to see reactions of just 1,2,3,4-tetrahydroquinoline, but with more diversity among the nitroaromatics.Can the authors include at least another 5 to 8 different nitroarenes in the scope?It would be interesting to see if functional groups such as cyanide, ester, ketone, trifluoromethyl, boronic ester, azide, thioether, sulfone, and amide are compatible with the reaction.

Comment & Suggestions 2.12:
What happens when para-nitrotoluene and para-fluorobenzene react?Can the authors report the outcome of such a reaction?Does the selectivity change, or does the reaction not work?Could the author provide this information?

Comment & Suggestions 2.13:
Would the author consider rephrasing this sentence for clarity?"It formally seems to be an SNArH reaction, however, shown in our optimization experiments that the reaction proceeds only in the DMSO/ t BuONa/O2 or DMF/ t BuOK/O2 system, which is characterized by the presence of alkali metal ion as a possible mediator of further reactions via single electron transfer (SET) from a reactant to generate the free radicals of the latter."

Our Replies:
The phrase has been replaced with "Although formally resembling an SNArH reaction, control experiments and radical clock experiments demonstrate that the reaction proceeds via a radical mechanism in the DMSO/ t BuONa/O2 or DMF/ t BuOK/O2 system".

Comment & Suggestions 2.14:
Could the authors please provide references to substantiate the claim that t BuONa or t BuOK serves as a mediator in reactions proceeding via single electron transfer, as mentioned in lines 161-162-163.

Our Replies:
In accordance with suggestion 2.13, our ideas were expressed imprecisely and subsequently rephrased.

Comment & Suggestions 2.15:
Can the author provide a proper citation to support the statement made at lines 182-183.
"The reaction can give azobenzene 6d with aniline 5d from radical homo-coupling under standard conditions, indicating the nitrogen radical''

Comment & Suggestions 2.16:
Could the authors repeat the experiment in Fig 2g for synthesizing azobenzenes with methyl aniline, as reported in the manuscript, since there are no examples using simple aniline.

Our Replies:
The experiment in Comment & Suggestions 2.17: 2h, 2j, 2k, and 2l relate to the mechanism under discussion?

Could you please elucidate how the experiments shown in Figures
Presenting these experiments without deriving conclusions may lead to confusion.It may be more appropriate to relocate this information to another section or include it in the Supplementary Information.Particularly the reaction in Figure 2h appears to have an energy profile (S40 in the SI) that closely resembles that of nitrobenzene could the author provide an explanation?

Our Replies:
Based on the results presented in Figures 2j, 2k, and 2l, it is evident that the type of alkali metal ions exerts a significant influence on reactions involving aliphatic amines.
The comparison of critical data between TS1 and TS1c in Figures 2h, respectively, is essential for investigating the role of the NO2 group (Figure SX1).
During C-N bond formation, in PhNO2→TS1 procedure, the negative charge of NO2 group (q(NO2)) is increased from -0.193 to -0.256, and the q(NO2) change Δq(NO2) = -0.063.While in PhCN→TS1c procedure, the negative charge of CN group (q(CN)) is only increased from -0.206 to -0.228, and the q(CN) charge Δq(CN)=-0.026.The NO2 group can stabilize more negative charge than CN group during C-N bond formation.Besides, both Mayer Bond Order (MBO) and electron density ρ of C...N bond in TS1 are higher than those in TS1c, indicating that TS1 has stronger C...N bond than TS1c, which is responsible for lower free energy of TS1.
According to the Arrhenius formula, we determined that the relative rates of TS1 and TS1c are in a ratio of 1:0.38, indicating that the rate of TS1c was comparatively slower than that of TS1.Consequently, the corresponding yield of 5f was also lower compared to 2a.It should be noted that due to limitations in computational precision and cost considerations, our results provide qualitative accuracy rather than quantitative precision.

Comment & Suggestions 2.18:
The Radical clock experiment reported in Fig. 2m did not provide any product that prove radical formation.Furthermore, the explanation offered for the formation of 6g lack experimental support.
-Could the authors clarify how they have ruled out the possibility that a simple reduction of nitroarene to form aniline, followed by the formation of compound 6g as described earlier, is not occurring?-It may be beneficial for the authors to consider repeating the experiment with a different nitroarene, such as ortho-Cl or ortho-F, or paramethyl N-cyclopropylaniline to ensure that a self-condensation reaction to form 6g as described earlier is not taking place.

Our Replies:
The utilization of a substitute 5i is attempted to confirm the presence of the aniline moiety in 6i originating from 5i.And the expected product 6i-1 was determined by GC-MS in the system.Unfortunately, our attempts to isolate the target product 6i-1 were unsuccessful.

Comment & Suggestions 2.19:
The experiment reported on page S35 of the SI, Figure 2B, which show the mass detection of the opened radical clock is quite significant and therefore should be included in the main manuscript, since provides tentative support for the formation of the aminyl radical.To substantiate this finding, the authors are encouraged to provide the FID) cfrom the mass spectrometry, including fragmentation patterns, in the SI.

Our Replies:
We did the mass detection of the opened radical clock by GC-MS.After reacting 4.0h, 6i-1, and 5j were determined by GC-MS.As the reaction progressed, we found that 6i increased significantly.Unfortunately, our attempts to isolate the target product 6i-1 were unsuccessful.

4.0h: 18.0h:
Comment & Suggestions 2.20: Would the author consider rephrasing this sentence for clarity?Line 205-207 Which radical species is the author referring to? "Furthermore, nitrogen radical could not deliver the desired radical without t BuONa or O2, indicating that the base and O2 are all necessary for the formation of nitrogen radical.''

Our Replies:
As shown in Fig. 3, the absence of t BuONa or O2 resulted in no observation of any nitrogen radical, indicating that both the base and O2 are essential for the formation of nitrogen radical.

Comment & Suggestions 2.21:
At lines 207-208, the text mentions 'the obvious nitrobenzene complex radical.'Is this radical the same as the one shown in EPR Figure 3b and described as INT1 in Figure 4?
For clarity, the should call it with is name and report the structure in Figure 3b next to EPR specta.

Our Replies:
The radical species previously referred to as "the obvious nitrobenzene complex radical" has been identified as "the nitrobenzene radical anion" (g = 2.0046, AN = 10.8G, AH = 3.5 G, AH = 3.5 G, AH = 3.5 G, AH = 0.8 G, AH = 0.8 G), and subsequently excluded from further discussion.

Comment & Suggestions 2.22:
Furthermore, the details about the EPR on page S33, which provide the most convincing evidence of the radical nature of the process, should be included in the main manuscript.

Our Replies:
The details regarding the EPR have been incorporated into the main manuscript.

Comment & Suggestions 2.23:
Regarding the conclusion, the authors suggest that triplet oxygen could generate nitrogen radicals through hydrogen abstraction from the N-H bond, presenting a mild and versatile pathway to N-centered radicals.However, the mechanism illustrated in Figure 4 depicts oxygen functioning merely as an oxidant for Na-amide, with triplet oxygen acting as a simple oxidant.Could the Authors clarify this point?

Our Replies:
Lines 270-272, O2(triplet) functions as an oxidant, and we have elucidated this aspect in our manuscript.

Our Replies:
These compounds have undergone further purification, resulting in the provision of higher-quality data in the Supplementary Information.

Response to reviewer 3' s comments
Comment & Suggestions 3.1: In Figure 1b, the radical position in Baran's work should be corrected.

Our Replies:
The discussion regarding Professor Baran's work has been omitted.

Comment & Suggestions 3.2:
In Figure 2m, the reaction of 5g with 2a gave 6g.However, 6g was also possible to be obtained from homo-coupling of 2a (see Fig. 2l).A substituted 5g is recommended for the reaction to verify the aniline moiety of 6g being from 5g.

Our Replies:
The utilization of a substituted 5i is attempted to confirm the presence of the aniline moiety in 6i originating from 5i.And the expected product 6i-1 was determined by GC-MS in the system.Unfortunately, our attempts to isolate the target product 6i-1 were unsuccessful.

Comment & Suggestions 3.3:
How about if the para-position of nitroarenes is blocked.Can the authors provide some examples?

Response to reviewer 4' s comments
Comment & Suggestions 4.1: From the substrate scope in Table 1 and Table 2, the synthesis strategy is only applicable to secondary amines instead of primary amines.The range of substrate is should be corrected in the abstract.In addition, the synthesis strategy seems to rely strongly on the conjugation of aryl groups with amines.In the experiment with only four groups of aliphatic amines as substrates (3d-1, 3d-2, 1a-24, 1d-3), only tetrahydrofuran got the expected products.It can be seen that this strategy is also not suitable for aliphatic amines.

Our Replies:
We have provided 11 additional examples of aliphatic amines.Substrates, such as 1c-1 and 1c-2, are included in the examples.However, the reactions involving other arylprimary amines yielded unsatisfactory results, with the prominent formation of azobenzene compounds observed as ones of defined by-products.The limitations of this type of substrates have been delineated within the main manuscript (lines 113-115).And 1cyclohexylamine 1d-12 did react with 2a to afford 3d-12 with a low yield of 28%.

Comment & Suggestions 4.2:
The substrate scope in Table 1 and Table 2 only contains some simple substituent groups (alkoxy, halogen and methyl groups).The authors could try more representative substrate.
Meanwhile, I wonder if the strategy be functional group tolerance or not?For example, how about the tolerance for the carboxylic acid, alcohol, amide, aldehyde, ketone and other common functional groups?

Our Replies:
The reaction between indole derivative 7-methylindoline 1b-24, bearing a methyl group at C7, and compound 2a resulted in the formation of product 3b-24 with a low yield of 30%.

Comment & Suggestions 4.4:
Could pyrrole be used as substrate in this strategy?

Our Replies:
To our disappointment, this strategy is not suitable for pyrrole.

Comment & Suggestions 4.5:
In this work, does the nitrobenzene with substituents at C4 position react or not?And what is the role of the nitro group?Could it be replaced by other electron-withdrawing groups?
The nitro group be replaced by other electron-withdrawing groups, such as CN group.
In order to investigate the role of NO2 group, we need to compare some critical data between TS1 and TS1c in Figures 2h, respectively (Figure SX1).
During C-N bond formation, in PhNO2→TS1 procedure, the negative charge of NO2 group (q(NO2)) is increased from -0.193 to -0.256, and the q(NO2) change Δq(NO2) = -0.063.While in PhCN→TS1c procedure, the negative charge of CN group (q(CN)) is only increased from -0.206 to -0.228, and the q(CN) charge Δq(CN)=-0.026.The NO2 group can stabilize more negative charge than CN group during C-N bond formation.Besides, both Mayer Bond Order (MBO) and electron density ρ of C...N bond in TS1 are higher than those in TS1c, indicating that TS1 has stronger C...N bond than TS1c, which is responsible for lower free energy of TS1.It is no doubt that the reaction is a free radical reaction proved by the control experiment.
However, the DFT calculation is confused.The energy barrier of the reaction reached 43.2 kcal/mol from 1a-1 to TS1, and the reaction could not happen under the experimental conditions.In addition, the generation of NaO2 species is suspicious.Is it a free radical?
Could it be verified by experiments?

Our Replies:
The reaction temperature is 313.15K (40 ℃), deviating from the standard room temperature of 298.15K (25 ℃).Consequently, we deemed the free energy barrier of 43.2 kcal/mol to be within an acceptable range.
The NaO2, actually as Na + O2 is produced in the formation of 1a-1-radical, but it is subsequently consumed in TS2.When the reaction is finished, no Na + O2 was left, only NaO2H (Na-O-O-H) was released.

Reviewer #1 (Remarks to the Author):
In their response letter, the authors have addressed my comments, but their answers are in most cases elusive and do not get to the point.I still believe that as it stands the manuscript is not suited for publication in Nature Communications.The description of the mechanistic studies remains superficial and speculative, clearly not adequate for the level of this journal.For example, despite my comment that N-cyclopropylaniline is not an appropriate probe for the intended purpose, the authors do not address the point and provide a scheme showing the detection of reaction products by GC-MS that, is tentative and clearly insufficient as a mechanistic evidence.I also insist on the proposed 1,4-H shift that I sincerely don't see why and especially how it should occur, considering in particular the rigidity of the system.Following the mechanistic studies, on page 7 the authors state that "According to these experiment results, we further came to the conclusion that the reaction may proceed through a radical pathway."I agree with the hypothesis that the reaction may proceed through a radical mechanism but I think that the mechanistic evidence provided is insufficient and not conclusive Reviewer #2 (Remarks to the Author): The authors have perfectly addressed all the points.The manuscript can be published in Nature Communications.

Reviewer #4 (Remarks to the Author):
This work is very interesting.The authors have revised the manuscript according to my comments, it could be acceptable now.

Response to reviewer 1' s comments
Comment & Suggestions 1.1: In their response letter, the authors have addressed my comments, but their answers are in most cases elusive and do not get to the point.I still believe that as it stands the manuscript is not suited for publication in Nature Communications.The description of the mechanistic studies remains superficial and speculative, clearly not adequate for the level of this journal.
For example, despite my comment that N-cyclopropylaniline is not an appropriate probe for the intended purpose, the authors do not address the point and provide a scheme showing the detection of reaction products by GC-MS that, is tentative and clearly insufficient as a mechanistic evidence.
I also insist on the proposed 1,4-H shift that I sincerely don't see why and especially how it should occur, considering in particular the rigidity of the system.
Following the mechanistic studies, on page 7 the authors state that "According to these experiment results, we further came to the conclusion that the reaction may proceed through a radical pathway."I agree with the hypothesis that the reaction may proceed through a radical mechanism but I think that the mechanistic evidence provided is insufficient and not conclusive.

Our Replies:
We deeply appreciate the invaluable insights you have provided regarding our research findings.
As previously mentioned in your initial comments "The description of the radical clock experiment is pure speculation.N-Cyclopropylaniline is not an appropriate probe for the intended purpose.The putative intermediate aminyl radical is stabilized by the phenyl group and this would significantly slow down ring opening."A report by Ingold et al.

Response to reviewer 2' s comments
Comment & Suggestions 2.1: The authors have perfectly addressed all the points.The manuscript can be published in Nature Communications.

Our Replies:
We sincerely appreciate your valuable insights and affirmations regarding our research findings.

Response to reviewer 4' s comments
Comment & Suggestions 4.1: This work is very interesting.The authors have revised the manuscript according to my comments, it could be acceptable now.

Our Replies:
We sincerely appreciate your valuable insights and affirmations regarding our research findings.

Figure 2 .
Figure 2. Panels (b) ii and (c) are very similar and should be merged into a single one.
makes no sense.Product 6g is observed in a number of reactions where no aromatic Comment & Suggestions 1.1:

Figure 2 .
Figure 2. Panels (b)-ii and (c) are very similar and should be merged into a single one.
radical chemistry: Ritter et al. in Chemical Science, 2019, 10, pages 2424-2428; Ritter et al. in Angewandte Chemie International Edition, 2019, 58, pages 532-536; and Carreira et al. in Angewandte Chemie International Edition, 2019, 58, pages 526-531.I am surprised that this paper are completely omitted considering the relevance with the reported reaction.
Fig 2g was repeated to synthesize azobenzene using methyl aniline 1c-1, however, instead of azobenzene, (E)-N-methyl-N,N'-diphenylformimidamide 6j was only obtained as the product with a low yield of 15%.It is worth noting that examples include simple anilines such as 1c-1 and 1c-2.

Figure SX1 .
Figure SX1.The results of Hirshfeld charge calculations, Mayer Bond Order (MBO) analyses and QTAIM analyses of PhNO2, TS1, PhCN and TS1c.Comment & Suggestions 4.6: Fig. 1).The N-cyclopropylaniline probes employed in radical clock experiments are highly versatile (for review, please see Angew.Chem.2023, 135, e202213003) and facilitate a comprehensive understanding of the reaction mechanism.The utilization of GC-MS for the detection of reaction products provides sufficient mechanistic evidence in our study.